We are looking at several aspects of autoimmunity and pathogenetic mechanisms in models of renal disease in mice and guinea pigs. We feel it is an important question to determine how autoantibodies, complement and lymphocytes and macrophages interest to cause lesion and how immune complexes form or are deposited in tissues. Work on the genetic basis of susceptibility to the induction of autoimmune renal tubular disease continues and indicates that traits linked to the major histocompatibility complex such as levels of tolerance, immune or inflammatory responses, or basement membrane antigenicity are areas to be explored. It may also be that there is a genetic basis for the development of anti-basement membrane autoantibodies in man. Only certain transplant patients and only certain patients treated with methicillin or dilantin develop anti-TBM autoantibodies and renal lesions. It may be that, as in mice, there is a MHC-linked trait which governs levels of tolerance to self or altered-self. Further studies on the acceleration of (NZBxNZW) lupus nephritis by anti-glomerular basement membrane (GBM) are related to human renal disease and may confirm the hypothesis of Peters that in anti-GBM nephritis recurrent exacerbations could be related to immune complex deposition during episodes of infection. Based on our observations, it is evident that present methods for the detection of pathogenetically relevant immune complexes are inadequate. Failure to detect immune complexes in plasma may be associated with flaws in the test system. For example, patients with post-streptococcal or chronic membrane nephritis are usually negative for circulating immune complexes although we suspect that based on the mouse data and deposition in the patient's kidneys there may be as yet undetected complexes present in plasma.